Evaluating multiplicity reporting in analgesic clinical trials: An analytical review.

Background And Objectives: Analgesia trials often demands multiple comparisons to assess various treatment arms, outcomes, or repeated assessments. These multiple comparisons risk inflating the false positive rate. Multiplicity correction in recent analgesic randomized controlled trials (RCTs) remains unclear despite statistical method advancements and regulatory guidelines.

Functions of LKB1 in neural crest development: The story unfolds.

Neural crest cells (NCCs) are highly motile, multipotent, embryonic cells that delaminate from the dorsal edges of the neural tube. NCCs follow stereotypical long-range migratory pathways to reach target organs during development, where they give rise to multiple derivatives. The identification of reservoirs of neural crest stem cells that persist to adulthood has recently aroused renewed interest in the biology of NCCs.

Discovery of Potent and Selective Dual Leucine Zipper Kinase/Leucine Zipper-Bearing Kinase Inhibitors with Neuroprotective Properties in In Vitro and In Vivo Models of Amyotrophic Lateral Sclerosis.

Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are regulators of neuronal degeneration and axon growth. Therefore, there is a considerable interest in developing DLK/LZK inhibitors for neurodegenerative diseases. Herein, we use ligand- and structure-based drug design approaches for identifying novel amino-pyrazine inhibitors of DLK/LZK.

Understanding the practice patterns of nephrology nurse practitioners in Australia.

Background: Nurse practitioners (NP) have an expanded scope of practice beyond that of a registered nurse. In kidney care, nephrology NP can manage patients at various points along the chronic kidney disease (CKD) trajectory.

Objectives: To profile the characteristics, service patterns, and domains of practice of nephrology NP in Australia.

Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma.

Background: Glypican-3 (GPC-3) is an oncofetal protein that is highly expressed in various solid tumors, but rarely expressed in healthy adult tissues and represents a rational target of particular relevance in hepatocellular carcinoma (HCC). Autologous chimeric antigen receptor (CAR) αβ T cell therapies have established significant clinical benefit in hematologic malignancies, although efficacy in solid tumors has been limited due to several challenges including T cell homing, target antigen heterogeneity, and immunosuppressive tumor microenvironments. Gamma delta (γδ) T cells are highly cytolytic effectors that can recognize and kill tumor cells through major histocompatibility complex (MHC)-independent antigens upregulated under stress.

Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity.

Background: Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary.

Results: We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases.

TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge.

Loss-of-function (LOF) variants of TREM2, an immune receptor expressed in microglia, increase Alzheimer's disease risk. TREM2 senses lipids and mediates myelin phagocytosis, but its role in microglial lipid metabolism is unknown. Combining chronic demyelination paradigms and cell sorting with RNA sequencing and lipidomics, we find that wild-type microglia acquire a disease-associated transcriptional state, while TREM2-deficient microglia remain largely homeostatic, leading to neuronal damage.

LKB1 specifies neural crest cell fates through pyruvate-alanine cycling.

Metabolic processes underlying the development of the neural crest, an embryonic population of multipotent migratory cells, are poorly understood. Here, we report that conditional ablation of the tumor suppressor kinase in mouse neural crest stem cells led to intestinal pseudo-obstruction and hind limb paralysis. This phenotype originated from a postnatal degeneration of the enteric nervous ganglia and from a defective differentiation of Schwann cells.

A Visually Apparent and Quantifiable CT Imaging Feature Identifies Biophysical Subtypes of Pancreatic Ductal Adenocarcinoma.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with variable presentations and natural histories of disease. We hypothesized that different morphologic characteristics of PDAC tumors on diagnostic computed tomography (CT) scans would reflect their underlying biology.

Experimental Design: We developed a quantitative method to categorize the PDAC morphology on pretherapy CT scans from multiple datasets of patients with resectable and metastatic disease and correlated these patterns with clinical/pathologic measurements.

The sVEGFR1-i13 splice variant regulates a β1 integrin/VEGFR autocrine loop involved in the progression and the response to anti-angiogenic therapies of squamous cell lung carcinoma.

Background: While lung adenocarcinoma patients can somewhat benefit from anti-angiogenic therapies, patients with squamous cell lung carcinoma (SQLC) cannot. The reasons for this discrepancy remain largely unknown. Soluble VEGF receptor-1, namely sVEGFR1-i13, is a truncated splice variant of the cell membrane-spanning VEGFR1 that has no transmembrane or tyrosine kinase domain.

Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma.

There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver mutations.

Rethinking behavioral health processes by using design for six sigma.

Clinical evidence-based practices are strongly encouraged and commonly utilized in the behavioral health community. However, evidence-based practices that are related to quality improvement processes, such as Design for Six Sigma, are often not used in behavioral health care. This column describes the unique partnership formed between a behavioral health care provider in the greater Pittsburgh area, a nonprofit oversight and monitoring agency for behavioral health services, and academic researchers.

SAMHD1 has differential impact on the efficacies of HIV nucleoside reverse transcriptase inhibitors.

Sterile alpha motif- and histidine/aspartic acid domain-containing protein 1 (SAMHD1) limits HIV-1 replication by hydrolyzing deoxynucleoside triphosphates (dNTPs) necessary for reverse transcription. Nucleoside reverse transcriptase inhibitors (NRTIs) are components of anti-HIV therapies. We report here that SAMHD1 cleaves NRTI triphosphates (TPs) at significantly lower rates than dNTPs and that SAMHD1 depletion from monocytic cells affects the susceptibility of HIV-1 infections to NRTIs in complex ways that depend not only on the relative changes in dNTP and NRTI-TP concentrations but also on the NRTI activation pathways.

Cdkn2a/p16Ink4a regulates fasting-induced hepatic gluconeogenesis through the PKA-CREB-PGC1α pathway.

Type 2 diabetes (T2D) is hallmarked by insulin resistance, impaired insulin secretion, and increased hepatic glucose production. The worldwide increasing prevalence of T2D calls for efforts to understand its pathogenesis in order to improve disease prevention and management. Recent genome-wide association studies have revealed strong associations between the CDKN2A/B locus and T2D risk.

Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk.

The nuclear bile acid receptor farnesoid X receptor (FXR) is an important transcriptional regulator of bile acid, lipid, and glucose metabolism. FXR is highly expressed in the liver and intestine and controls the synthesis and enterohepatic circulation of bile acids. However, little is known about FXR-associated proteins that contribute to metabolic regulation.

Transcranial ultrasound (TUS) effects on mental states: a pilot study.

Background/objective: Transcranial ultrasound (TUS) can modulate brain function. To assess possible TUS modulation of mental states, we investigated effects on subjective reports of pain and mood of sub-thermal TUS versus placebo applied to frontal scalp and brain of chronic pain patient volunteers.

Methods: With IRB approval and informed consent, subjects with chronic pain completed two visual analog scales for pain (NRS) and mood (VAMS/Global Affect), and their vital signs were recorded 10 min prior to, and 10 min and 40 min following exposure to either subthermal TUS (8 MHz) or placebo (in a double blind crossover study) using the 12L-RS probe of a LOGIQe ultrasound imaging machine (General Electric, USA).

Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity.

Objective: Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed.

The farnesoid X receptor regulates adipocyte differentiation and function by promoting peroxisome proliferator-activated receptor-gamma and interfering with the Wnt/beta-catenin pathways.

The bile acid receptor farnesoid X receptor (FXR) is expressed in adipose tissue, but its function remains poorly defined. Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipocyte differentiation and function. The aim of this study was to analyze the role of FXR in adipocyte function and to assess whether it modulates PPARγ action.

The nuclear receptor FXR is expressed in pancreatic beta-cells and protects human islets from lipotoxicity.

Farnesoid X receptor (FXR) is highly expressed in liver and intestine where it controls bile acid (BA), lipid and glucose homeostasis. Here we show that FXR is expressed and functional, as assessed by target gene expression analysis, in human islets and beta-cell lines. FXR is predominantly cytosolic-localized in the islets of lean mice, but nuclear in obese mice.

An educational course including medical simulation for early goal-directed therapy and the severe sepsis resuscitation bundle: an evaluation for medical student training.

Objective: Widespread application of early goal-directed therapy (EGDT) and the severe sepsis resuscitation bundle is limited by clinician knowledge, skills and experience. This study evaluated use of simulation-based teaching during medical training to increase future clinician knowledge in the above therapies for severe sepsis and septic shock.

Methods: A prospective cohort study was performed with medical students at all levels of training.

Long-chain (n-3) polyunsaturated fatty acids prevent metabolic and vascular disorders in fructose-fed rats.

The crossover relationship between cardiometabolic risk, in terms of insulin resistance and vascular dysfunction, and the fatty acid (FA) profile of insulin-sensitive tissues as well as the dietary FA impact has almost never been explored in the same experiment. In this study, the intake of alpha-linolenic acid (ALA) alone and/or with its higher metabolites, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) were evaluated in a nonobese, hypertriglyceridemic and insulin-resistant rat model, that exhibits the 2 main characteristics of metabolic syndrome. Wistar rats were fed either a cornstarch and (n-6) PUFA-based diet (C-N6) or a 66% fructose diet over a 10-wk period.

Prediction of dry matter, fat, pH, vitamins, minerals, carotenoids, total antioxidant capacity, and color in fresh and freeze-dried cheeses by visible-near-infrared reflectance spectroscopy.

Visible-near-infrared reflectance spectroscopy was used to predict dry matter, fat, pH, retinol, alpha-tocopherol, beta-carotene, xanthophylls, sodium chloride, calcium, potassium, magnesium, zinc, total antioxidant capacity, brightness, redness, and yellowness in both fresh and freeze-dried cheeses. A total of 445 cheeses of four cheese varieties were investigated. Composition of samples was analyzed by reference methods.

Dietary n-3 polyunsaturated fatty acids and endothelium dysfunction induced by lysophosphatidylcholine in Syrian hamster aorta.

This study investigated the influence of an eicosapentaenoic acid (EPA)- or a docosahexaenoic acid (DHA)-supplemented diet on the deleterious effects of lysophosphatidylcholine (LPC) on endothelium-dependent vasorelaxation of Golden Syrian hamster thoracic aorta. In a second step, LPC-modulated phospholipase A(2) (PLA(2))-derived ways of relaxation were investigated. Golden Syrian hamsters were fed for 6 weeks with a control diet or an EPA- or DHA-supplemented diet.